The incidence of thyroid cancer is increasing yearly in the United States at the second fastest rate of all cancers. Although the overall prognosis from thyroid cancer is excellent, no effective therapies exist for patients with distant metastases. Activating mutation in the gene encoding BRAF, and mutations and genetic rearrangements involving upstream regulators of BRAF, including RET/PTC rearrangements and activation mutations of RAS occur in approximately 50% of all well-differentiated thyroid cancers. These oncogenes continue to be expressed in even long-standing thyroid cancers and cell signaling properties of human tumors have confirmed their continued biological activity. Taken together, these data support the concept that RAF kinase inhibitors have potential therapeutic benefit for patients with thyroid cancers that do not respond to traditional therapies. Consistent with these data, one patient with metastatic thyroid cancer demonstrated a partial response to a RAF kinase inhibitor (BAY 43-9006; NSC 724772) in a phase 1 study. Our center was recently selected to be the coordinating center for an investigator-initiated, NCI-sponsored multicenter phase 2 trial of this agent for metastatic thyroid cancer. To date, there are no in vitro or nonhuman in vivo studies of this agent using thyroid cancer cell lines or animal models. As this agent also inhibits several other receptor tyrosine kinases involved in thyroid cancer, including VEGF and PDGF receptors, we believe that these corollary studies are critical in defining the pharmacodynamic effects of this agent in thyroid cancer, and in predicting which papillary thyroid cancer patients would derive greatest benefit from its use. Therefore, the goal of the current grant application is to seek support for correlates to determine predictors of response to this agent based on tumor genotype, and to correlate cell signaling and angiogenic marker expression with clinical response and with novel non-invasive imaging techniques. [unreadable] [unreadable]